Pentamidine
Encyclopedia
Pentamidine is an antimicrobial
medication
given for prevention and treatment of Pneumocystis pneumonia
(PCP) caused by Pneumocystis jirovecii (formerly known as Pneumocystis carinii), a severe interstitial type of pneumonia
often seen in patients with HIV
infection. The drug is also the mainstay of treatment for stage I infection with Trypanosoma brucei
gambiense (West African Trypanosomiasis
).
, and yeast infections caused by the organism Candida albicans
. Pentamidine is also used as a prophylactic antibiotic for children undergoing treatment for leukemia.
The exact mechanism of its anti-protozoa
l action is unknown (though it may involve reactions with ubiquitin
), despite the fact that it is a basic therapeutic modality (in concurrence with multiple antifungal medications) when treating Acanthamoeba infections in the immunocompromised patients. In the United States
, pentamidine is currently designated an orphan drug
by the U.S. Food and Drug Administration.
(brand names Bactrim, Septrin, or Septra). Clinical evidence suggests that pentamidine is often better tolerated than co-trimoxazole because a high dose of co-trimoxazole is needed, which is associated with a high incidence and severity of side effects such as hepatitis, bone-marrow-damage, renal-damage, and life threatening skin disease (Lyell-syndrome). Moreover, many patients are or become allergic
to co-trimoxazole. For treatment of PCP, 4 milligrams of pentamidine per kilogram of body weight is given intravenously once daily for 14 to 21 days. Treatment exceeding 21 days may be necessary, but is associated with increased toxicity. Intramuscular injection
is not recommended. The effect of pentamidine often becomes evident within the first 2 days of treatment, with reduction in fever and improvement of respiratory function. In any case, improvements of chest x-ray
studies occur within 6 to 8 days, provided therapy is successful. Pentamidine therapy cures 50 to 70% of all patients treated.
or CDC exist.
Use as an antitumor drug has also been proposed.
s, amphotericin B
, capreomycin
, colistin
, polymyxin B
, vancomycin
, foscarnet
, or cisplatin
should be closely monitored, or whenever possible completely avoided.
Antimicrobial
An anti-microbial is a substance that kills or inhibits the growth of microorganisms such as bacteria, fungi, or protozoans. Antimicrobial drugs either kill microbes or prevent the growth of microbes...
medication
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
given for prevention and treatment of Pneumocystis pneumonia
Pneumocystis pneumonia
Pneumocystis pneumonia or pneumocystosis is a form of pneumonia, caused by the yeast-like fungus Pneumocystis jirovecii...
(PCP) caused by Pneumocystis jirovecii (formerly known as Pneumocystis carinii), a severe interstitial type of pneumonia
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
often seen in patients with HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
infection. The drug is also the mainstay of treatment for stage I infection with Trypanosoma brucei
Trypanosoma brucei
Trypanosoma brucei is a parasitic protist species that causes African trypanosomiasis in humans and nagana in animals in Africa. There are 3 sub-species of T. brucei: T. b. brucei, T. b. gambiense and T. b. rhodesiense.These obligate parasites have two hosts - an insect vector and mammalian host...
gambiense (West African Trypanosomiasis
Trypanosomiasis
Trypanosomiasis or trypanosomosis is the name of several diseases in vertebrates caused by parasitic protozoan trypanosomes of the genus Trypanosoma. Approximately 500,000 men, women and children in 36 countries of sub-Saharan Africa suffer from human African trypanosomiasis which is caused by...
).
Uses
Pentamidine is also used as a prophylactic against PCP in patients receiving chemotherapy, as they also have a depressed immune system as a direct side-effect of the drugs used. The mortality of untreated PCP is very high. Additionally, pentamidine has good clinical activity in treating leishmaniasisLeishmaniasis
Leishmaniasis is a disease caused by protozoan parasites that belong to the genus Leishmania and is transmitted by the bite of certain species of sand fly...
, and yeast infections caused by the organism Candida albicans
Candida albicans
Candida albicans is a diploid fungus that grows both as yeast and filamentous cells and a causal agent of opportunistic oral and genital infections in humans. Systemic fungal infections including those by C...
. Pentamidine is also used as a prophylactic antibiotic for children undergoing treatment for leukemia.
The exact mechanism of its anti-protozoa
Protozoa
Protozoa are a diverse group of single-cells eukaryotic organisms, many of which are motile. Throughout history, protozoa have been defined as single-cell protists with animal-like behavior, e.g., movement...
l action is unknown (though it may involve reactions with ubiquitin
Ubiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
), despite the fact that it is a basic therapeutic modality (in concurrence with multiple antifungal medications) when treating Acanthamoeba infections in the immunocompromised patients. In the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
, pentamidine is currently designated an orphan drug
Orphan drug
An orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease...
by the U.S. Food and Drug Administration.
Treatment of acute PCP
In the acute treatment of PCP, pentamidine is considered equally or slightly less active than co-trimoxazoleCo-trimoxazole
Trimethoprim/sulfamethoxazole or co-trimoxazole is a sulfonamide antibiotic combination of trimethoprim and sulfamethoxazole, in the ratio of 1 to 5, used in the treatment of a variety of bacterial infections.The name co-trimoxazole is the British Approved Name, and has been marketed worldwide...
(brand names Bactrim, Septrin, or Septra). Clinical evidence suggests that pentamidine is often better tolerated than co-trimoxazole because a high dose of co-trimoxazole is needed, which is associated with a high incidence and severity of side effects such as hepatitis, bone-marrow-damage, renal-damage, and life threatening skin disease (Lyell-syndrome). Moreover, many patients are or become allergic
Allergy
An Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...
to co-trimoxazole. For treatment of PCP, 4 milligrams of pentamidine per kilogram of body weight is given intravenously once daily for 14 to 21 days. Treatment exceeding 21 days may be necessary, but is associated with increased toxicity. Intramuscular injection
Intramuscular injection
Intramuscular injection is the injection of a substance directly into a muscle. In medicine, it is one of several alternative methods for the administration of medications . It is used for particular forms of medication that are administered in small amounts...
is not recommended. The effect of pentamidine often becomes evident within the first 2 days of treatment, with reduction in fever and improvement of respiratory function. In any case, improvements of chest x-ray
Chest X-ray
In medicine, a chest radiograph, commonly called a chest X-ray , is a projection radiograph of the chest used to diagnose conditions affecting the chest, its contents, and nearby structures...
studies occur within 6 to 8 days, provided therapy is successful. Pentamidine therapy cures 50 to 70% of all patients treated.
Primary and secondary prophylaxis of PCP
Primary prophylaxis of severely immunocompromised patients can be indicated where PCP has not yet been diagnosed. Secondary prophylaxis aims to prevent recurrent infections by PCP. For both forms of prophylaxis, an aerosolized formulation of pentamidine given by nebulizer once monthly in a dose of 300 mg is used. In primary prophylaxis, this reduces the long term likelihood of PCP by 70% when compared to no prophylaxis. The aerosolized route of administration is particularly suited for pregnant women in their first trimester (when TMP-SMX is contraindicated). Aerosolized administration may lead to an atypical PCP infection involving the upper lobes.Other
For other indications, such as leishmaniasis or sleeping sickness, special treatment schedules developed by the WHOWorld Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
or CDC exist.
Use as an antitumor drug has also been proposed.
Contraindications
- Severe allergy; no others in PCP patients in whom a proper diagnosis has been made
Mechanism
The mechanism is not well characterized, but there is some evidence that it may involve mitochondrial function.Side effects
Pentamidine can cause allergic and toxic side effects, most commonly having effects on the pancreas, which in part depend on the daily and/or cumulative dose:- KidneyKidneyThe kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
: 25 percent develop signs of nephrotoxicityNephrotoxicityNephrotoxicity is a poisonous effect of some substances, both toxic chemicals and medication, on the kidneys. There are various forms of toxicity. Nephrotoxicity should not be confused with the fact that some medications have a predominantly renal excretion and need their dose adjusted for the...
ranging from mild, asymptomatic azotemiaAzotemiaAzotemia is a medical condition characterized by abnormally high levels of nitrogen-containing compounds, such as urea, creatinine, various body waste compounds, and other nitrogen-rich compounds in the blood...
(increased serum creatinineCreatinineCreatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...
and ureaUreaUrea or carbamide is an organic compound with the chemical formula CO2. The molecule has two —NH2 groups joined by a carbonyl functional group....
) to irreversible renal failureRenal failureRenal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
. Ample fluids or intravenous hydration may prevent some nephrotoxicity. - Cardiovascular: HypotensionHypotensionIn physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
, which may be severe, severe or fatal arrhythmias and heart failure are quite frequent. - Gastrointestinal: NauseaNauseaNausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, vomiting, gastrointestinal discomfort, diarrheaDiarrheaDiarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, unpleasant taste - PancreasPancreasThe pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
: HypoglycemiaHypoglycemiaHypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
that requires symptomatic treatment is frequently seen. On the other hand, pentamidine may cause or worsen diabetes mellitusDiabetes mellitusDiabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
. - LiverLiverThe liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
: Elevated liver enzymes are associated with intravenous use of pentamidine. HepatomegalyHepatomegalyHepatomegaly is the condition of having an enlarged liver. It is a nonspecific medical sign having many causes, which can broadly be broken down into infection, direct toxicity, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass...
and hepatitisHepatitisHepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
have been encountered with long term prophylactic use of pentamidine inhalation. - SkinSkin-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
: Severe local reactions after extravasculation of intravenous solutions or following intramuscular injection treatment have been seen. Pentamidine itself may cause rash, or rarely Stevens–Johnson syndrome or Lyell syndromeToxic epidermal necrolysisToxic epidermal necrolysis is a rare, life-threatening dermatological condition that is usually induced by a reaction to medications...
. - BloodBloodBlood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
: Pentamidine frequently causes leukopeniaLeukopeniaLeukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
and less often thrombopenia, which may cause symptomatic bleeding. Some cases of anemiaAnemiaAnemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, possibly related to folic acidFolic acidFolic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
deficiency, have been described. - NeurologicalNervous systemThe nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
: Dizziness, drowsiness, neuralgiaNeuralgiaNeuralgia is pain in one or more nerves that occurs without stimulation of pain receptor cells. Neuralgia pain is produced by a change in neurological structure or function rather than by the excitation of pain receptors that causes nociceptive pain. Neuralgia falls into two categories: central...
, confusion, hallucinations, seizureSeizureAn epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s and other central side effects are reported. - RespiratoryRespiratory systemThe respiratory system is the anatomical system of an organism that introduces respiratory gases to the interior and performs gas exchange. In humans and other mammals, the anatomical features of the respiratory system include airways, lungs, and the respiratory muscles...
: Cough and bronchospasmBronchospasmBronchospasm or a bronchial spasm is a sudden constriction of the muscles in the walls of the bronchioles. It is caused by the release of substances from mast cells or basophils under the influence of anaphylatoxins...
, most frequently seen with inhalation. - Others: Eye discomfort, conjunctivitisConjunctivitisConjunctivitis refers to inflammation of the conjunctiva...
, throat irritation, splenomegalySplenomegalySplenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
, Herxheimer reactionHerxheimer reactionThe Herxheimer reaction resembles bacterial sepsis and can occur after initiation of antibiotic therapy or treatment of tick-borne relapsing fever. An association has been found between the release of heat-stable proteins from spirochetes and the reaction. The same can be true for candida die-off...
, electrolyteElectrolyteIn chemistry, an electrolyte is any substance containing free ions that make the substance electrically conductive. The most typical electrolyte is an ionic solution, but molten electrolytes and solid electrolytes are also possible....
imbalances (e.g. hypocalcemia).
Drug Interactions
The additional or sequential use of other nephrotoxic drugs like aminoglycosideAminoglycoside
An aminoglycoside is a molecule or a portion of a molecule composed of amino-modifiedsugars.Several aminoglycosides function as antibiotics that are effective against certain types of bacteria...
s, amphotericin B
Amphotericin B
Amphotericin B is a polyene antifungal drug, often used intravenously for systemic fungal infections...
, capreomycin
Capreomycin
Capreomycin is a peptide antibiotic, commonly grouped with the aminoglycosides, which is given in combination with other antibiotics for tuberculosis...
, colistin
Colistin
Colistin is a polymyxin antibiotic produced by certain strains of Bacillus polymyxa var. colistinus. Colistin is a mixture of cyclic polypeptides colistin A and B. Colistin is effective against most Gram-negative bacilli and is used as a lingerdoodle. It is one of the last-resort antibiotics for...
, polymyxin B
Polymyxin B
Polymyxin B is an antibiotic primarily used for resistant gram-negative infections. It is derived from the bacterium Bacillus polymyxa. Polymyxin B is a mixture of two closely related compounds, polymyxin B1 and polymyxin B2. It has a bactericidal action against almost all gram-negative bacilli...
, vancomycin
Vancomycin
Vancomycin INN is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of...
, foscarnet
Foscarnet
Foscarnet is the conjugate base of the chemical compound with the formula HO2CPO3H2.-Uses:This phosphonic acid derivative is an antiviral medication used to treat herpes viruses, including drug resistant cytomegalovirus and herpes simplex viruses types 1 and 2...
, or cisplatin
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
should be closely monitored, or whenever possible completely avoided.
Brand names and dose forms
- For oral inhalation: NebuPent 300 mg Nebulizer
- For parenteral treatment: Pentacrinat, Pentam 300, and Pentamidine isethionate for injection (Abbot); all containing 300 mg of Pentamidine
See also
- DNA-binding proteinDNA-binding proteinDNA-binding proteins are proteins that are composed of DNA-binding domains and thus have a specific or general affinity for either single or double stranded DNA. Sequence-specific DNA-binding proteins generally interact with the major groove of B-DNA, because it exposes more functional groups that...
- Hoechst 33258Hoechst stainHoechst stains are part of a family of blue fluorescent dyes used to stain DNA. These Bis-benzimides were originally developed by the Hoechst AG, which numbered all their compounds so that the dye Hoechst 33342 is the 33342nd compound made by the company. There are three related Hoechst stains:...
- NetropsinNetropsinNetropsin is an oligopeptide with antibiotic and antiviral activity.Netropsin was discovered by Finlay et al. and first isolated from the actinobacterium Streptomyces netropsis. It belongs to the class of pyrrole-amidine antibiotics...
- LexitropsinLexitropsinLexitropsins is a family of semi-synthetic DNA-binding ligands.They are analogs of natural antibiotics Netropsin and Distamycin. Antibiotics of this group are capable to bind with a narrow groove of DNA with different sequence-selectivity. Lexitropsins form a complexes with DNA with stoichiometry...
- Nucleic acid simulations